This invention relates generally to the use of iontophoresis for permeant transport and, more specifically, to a method and device capable of reducing variability in the iontophoretic process by the use of a background co-ion that minimizes changes in the permeant flux and reduces inter-tissue variability.
Iontophoresis is commonly defined as the introduction of a compound or composition into the body or across a tissue by means of an electric current although; recently reverse iontophoresis has been used to non-invasively withdraw analytes (e.g. glucose) through the patient""s skin for analysis. In practice, transdermal iontophoresis is a non-invasive method of enhancing the passage of drugs or other compounds across the skin or mucosal tissue. Unfortunately, most iontophoretic methods cannot provide a constant flux at constant current, likely due to time-dependent changes in the porosity (permeability) of the skin, changes in the surface charge density, and changes in the effective pore size of the pathways in skin during the course of iontophoresis. The inability to adequately predict and control permeant transport has severely limited clinician, patient, industry, and regulatory authority acceptance of iontophoresis as a viable drug delivery or analyte extraction option.
Systems for transporting ionized substances through the skin have been known for some time. British Patent Specification No. 410,009 (1934) describes an iontophoretic delivery device that overcame one of the disadvantages of the early devices, namely, the need to immobilize a patient near a source of electric current. The device was made by forming a galvanic cell which itself produced the current necessary for iontophoretic delivery from the electrodes and the material containing the drug to be delivered. Unlike previous iontophoretic delivery systems, the device allowed the patient to move around during drug delivery and thus minimized interference with the patient""s daily activities.
In present iontophoretic devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some area of the body surface, i.e., skin or mucosal tissue. In iontophoretic drug delivery, one electrode, called the active or donor electrode, is the electrode from which the drug is delivered into the body. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. If the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve as the counter electrode, completing the circuit. If the ionic substance to be delivered is negatively charged, then the cathode will be the active electrode and the anode will be the counter electrode.
In analyte extraction, the electrode that receives the analyte from the body can be termed the receiver electrode and the second electrode can be termed the indifferent or return electrode. If the substance being extracted from the body is a cation (positively charged), the receiver electrode will be the cathode. Conversely, if the extracted substance is an anion, the anode will be the receiver electrode. If, however, the extracted substance is uncharged, the receiver electrode will be the cathode because of the direction of electroosmotic flux in the direction of anode to cathode under physiological conditions.
In conjunction with the patient""s skin, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery, and usually to circuitry capable of controlling current passing through the device.
Iontophoretic drug delivery devices also generally include a reservoir or source of the drug that is to be delivered into the body. Iontophoretic analyte extraction devices include a reservoir for collection of the analyte. Examples of such reservoirs or sources include a pouch, as described in Jacobsen, U.S. Pat. No. 4,250,878, a pre-formed gel body, as disclosed in Webster, U.S. Pat. No. 4,382,529 and Ariura et al. U.S. Pat. No. 4,474,570, a receptacle containing a liquid solution, as disclosed in Sanderson, et al., U.S. Pat. No. 4,722,726, a wetable woven or non-woven fabric, a sponge material, or any combination thereof. Such reservoirs are connected to the anode or the cathode of an iontophoretic device to provide a fixed or renewable source of one or more desired agents.
It is known that during direct current (DC) iontophoresis, the applied current causes pores in the skin cells to form (electroporation) and enlarge resulting in reduced electrical resistance. In addition, the direct current changes the net charge density of the pores. See, for example, U.S. Pat. No. 5,374,242 to Haak et al. and U.S. Pat. No. 5,019,034 to Weaver et al. Electroporation does not itself affect permeant transport but merely prepares the tissue thereby treated, for delivery of a drug by any of a number of techniques, one of which is iontophoresis.
In existing iontophoresis devices, the amount of agent transported across the tissue through these pores, generally referred to as the xe2x80x9cfluxxe2x80x9d, varies with time during the course of a typical iontophoresis procedure. Serious variability in the permeant flux exists during the first one to two hours of the application. The flux drift can then stabilize or continue to change depending on the permeant transported, the current profile, excipients present in the formulation, and the status of the biological membrane through which transport occurs. Intra- and inter-patient variability is also a major concern in iontophoretic devices, due to differences in the pores from one area of tissue to the next or from one patient to the next. In addition, different regions of a patient""s skin or skin between different patients respond differently to the electrical current, with some skin changing more than others. Some of the factors influencing the change in pore size are the patient""s age, level of hydration of the stratum corneum, previous damage, follicular density, or other unknown factors.
The variability in permeant flux during iontophoresis is the main complication accompanying pore induction (electroporation) in human skin at low to moderate voltages. Since the amount of material (e.g., drug delivery or analyte extraction) transported across skin varies with time, varies among patients, and varies from day-to-day in the same patient, controlled and predictable permeant transport using iontophoresis has heretofore not been possible.
As stated in U.S. Pat. No. 5,983,130 to Phipps et al., it has been recognized in the art that xe2x80x9ccompetitivexe2x80x9d ionic species having the same charge (i.e., the same sign) as the drug ions being delivered by electrotransport compete with the permeant ion for the electrical current and therefore have a negative impact on electrotransport efficiency. For example, Untereker et al., U.S. Pat. No. 5,135,477 and Petelenz et al., U.S. Pat. No. 4,752,285 state that competitive ionic species are electrochemically generated at both the anode and cathode of an electrotransport delivery device and present methods for reducing the negative effects of these competitive ionic species using cation permeants in the form of salts.
In addition, formulation excipients can provide extraneous competing ions. Some devices employ sodium chloride as a chloride source to control the migration of silver ions formed at a silver foil cathode. U.S. Pat. No. 6,049,733 to Phipps et al. teaches the use of supplementary chloride ion sources in the form of high molecular weight chloride resins in the donor reservoir of a transdermal electrotransport device. The resins are highly effective at providing sufficient chloride to capture the competitive silver ion and prevent their migration, yet because of the high molecular weight of the resin cation, the resin cation is effectively immobile and hence cannot compete with the permeant for transport through the body surface.
Competing co-ions have also been used to dampen transport efficiency in U.S. Pat. No. 5,983,130 to Phipps et al. However, the method of the patent is focused on biocompatible salts as co-ions that are used in quantities sufficient to raise the total current density above a critical current density at which the skin attains a highly transmissive state. Additionally, the Phipps patent makes reference to the disclosure of U.S. Pat. No. 5,080,646 to Theeuwes et al., stating that this reference provides sufficient teaching for one skilled in the art to select a suitable quantity and species of competitive co-ion to be transported along with the permeant. While Theeuwes et al. does contain a mathematical analysis of the effects of a hydrophilic resin within a hydrophobic matrix, it is silent as to the impact of electroporation-induced flux variability and the use of co-ions having hindrance factors that change at a faster rate than the hindrance factor of the permeant. As a consequence, neither Phipps et al. nor Theeuwes et al. provide a method or device that is capable of stabilizing permeant flux and reducing intra- and inter-patient variability.
Uncharged permeants also face inter- and intra-tissue, pore size change induced variability during iontophoretic extraction. For example, U.S. Pat. Nos. 6,023,629 and 5,771,890 both to Tamada, et. al., discuss the need for normalizing the flux drift of glucose during DC iontophoresis. The drift in flux requires a complicated algorithm to correlate extracted glucose with blood glucose. In Tamada, et al. (JAMA;282(19):1839-1844, 1999), the authors describe the algorithm needed to obtain reasonable correlation between blood glucose and extracted glucose using a mixture of experts method with input variables of the biosensor signal, the blood glucose value at calibration; the elapsed time since calibration, and an electrically derived offset. The algorithm was established based on population statistics. Therefore, if the patient""s skin parameters change outside of population norms, the glucose extraction device will give an ever increasingly incorrect reading as time of analysis progresses. Such drifts in flux necessitate the current art to have frequent, painful calibrations and an imprecise algorithm to decrease inaccuracy due to these well-known flux-drifts. There is, therefore, a need in the art for a method and device that address these concerns. The present invention provides a method and an apparatus that incorporates background ions having a hindrance factor that changes at a faster rate than the hindrance factor of the permeant during iontophoresis and stabilizes iontophoretic flux. It is proposed that the change in the hindrance factor will stabilize the transference number for reasons discussed infra.
In one main aspect of the current invention, a drug delivery device is provided that minimizes changes in iontophoretic flux and reduces intertissue variability that is comprised of (a) a first electrode assembly adapted to be placed in agent-transmitting relation with a body tissue that contains a pharmacologically active agent to be delivered and at least one background co-ion that has a hindrance factor that changes at a faster rate than the hindrance factor of the active agent when an electrical current is applied; (b) a second electrode assembly, adapted to be placed in ion transmitting relation with the body surface at a location spaced apart from the first electrode assembly; and (c) an electrical current source, electrically connected to the first and second electrode assemblies.
In another aspect of the invention, a method for delivering a pharmacologically active agent across body tissue using electrical current is provided, the improvement comprising co-delivering with the active agent at least one background co-ion having a hindrance factor that changes at a faster rate than the hindrance factor of the active agent when an electrical current is applied. The presence of the background co-ion minimizes changes in active agent flux and reduces intertissue variability.
In yet another aspect of the invention, a method for delivering a pharmacologically active agent across a region of body tissue is provided. First, a composition comprising the pharmacologically active agent and at least one background co-ion is placed in contact with the body tissue. The background electrolyte has a hindrance factor that changes at a faster rate than the hindrance factor of the active agent when an electrical current is applied and therefore becomes an ever-increasing competitor for the electrical current as the pore size enlarge. Second, an electrical current of a voltage and duration effective to induce electroporation is applied to the region of body tissue.
In a second main aspect of the invention, an analyte extraction device is provided that minimizes changes in iontophoretic flux and reduces intertissue variability that is comprised of (a) a first electrode assembly adapted to be juxtaposed with a body tissue that contains a reservoir for analyte collection and at least one background electrolyte that has a hindrance factor that changes at a faster rate than the hindrance factor of the transporting co-ion to the analyte in the body or tissue system when an electrical current is applied; (b) a second electrode assembly, adapted to be placed in ion transmitting relation with the body surface at a location spaced apart from the first electrode assembly; and (c) an electrical current source, electrically connected to the first and second electrode assemblies.
In another aspect of the invention, a method for extracting an analyte across body tissue using electrical current is provided, the improvement comprising transporting at least one background electrolyte (in the opposite direction of the analyte) having a hindrance factor that changes at a faster rate than the hindrance factor of the co-ion of the analyte in the body when an electrical current is applied. The presence of the background electrolyte minimizes changes in analyte flux and reduces intertissue variability.
In yet another aspect of the invention, a method for extracting an analyte across a region of body tissue is provided. First, a reservoir for collection of the analyte and containing at least background ion is placed in contact with the body tissue. The background ion(s) have a hindrance factor that changes at a faster rate than the hindrance factor of the co-ion of the analyte in the body when an electrical current is applied and therefore becomes an ever-increasing competitor for the electrical current as the pore size enlarge. Second, an electrical current of a voltage and duration effective to induce electroporation is applied to the region of body tissue.